Nuclear receptors are a class of ligand-dependent transcription factor superfamily, which are widely distributed in organisms, and play a role in aspects such as metabolism, development, biorhythm, inflammation, immune regulation and the like. The ligands for nuclear receptors include thyroid hormones, steroid hormones, retinoic acids, fatty acids, sterols and the like. In addition, there is a class of nuclear receptors for which the ligands have not been determined so far, and these receptors are called orphan nuclear receptors. Retinoid-related orphan receptors (RORs), also known as NF1R, are named due to their similarity to retinoic acid receptor (RAR) and retinoid X receptor (RXR) in their gene sequences. ROR subfamily mainly includes three members, RORα, RORβ and RORγ. At present, relatively more research is being conducted on RORα and RORγ and ligands thereof (modulators). RORα is widely expressed in various tissues and organs in the body. It may exist in brain, kidney, liver, testis, ovary, skeletal muscle, thymus, skin, lung and adipose tissue, wherein the highest expression level exists in brain tissue, especially cerebellar and thalamus. Recent researches also show that RORα participates in the activity of osteoblast of human body by stimulating osteoblast-promoting factors and inhibiting inflammatory reactions. RORγ mainly includes two subtypes, RORγ1 and RORγt (RORγ2), in which RORγ1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart, liver, etc.; while RORγt is only expressed in immune cells and is an RORγ subtype which is specific for T cells. Th17 cells are a class of Th cell subgroup which were recently proved to be capable of specifically producing cytokine IL-17. They participate in inducing autoimmune diseases, have strong pro-inflammatory effects, and are relevant to the occurrence and development of various autoimmune diseases, such as multiple sclerosis, psoriasis, arthritis, asthma, and the like. RORγ is a key driving factor of the differentiation and regulation of TH17 cells, and therefore gradually becomes an emerging potential target for developing drugs for autoimmune diseases. ROR inverse agonist (antagonist) blocks the occurrence and development of inflammation by affecting the functions of RORγ, regulating the proliferation and growth of TH17 cells, and inhibiting the generation of cytokine IL-17. In recent years, there have been a number of research articles showing that such an important physiological function of RORγ has been verified in experiments of in vitro inhibition of the generation of cytokine IL-17 and in mouse autoimmune disease models (CIA model, EAE model, etc.). (Nature 2011, 472, 486-490; Nature 2011, 472, 491-496; ACS Chem. Biol. 2012, 7, 672-677; Bioorg. Med. Chem. Lett. 23 (2013) 532-536; Journal Exp Med. 2008; 205(5):1063-1075; Immunol Res. 2001; 23(2-3):99-109; Cell 126, 1121-1133, Sep. 22, 2006; WO2012158784; WO2012100732; U.S. Pat. No. 8,389,739B1; WO2013160418; WO2013092939; WO2013169704; WO2013178362; ACS Med. Chem. Lett., 2014, 5(1), 65-68; Bioorg. Med. Chem. 2014(22), 692-702; J Immunol 2014 (192), 2564-2575; Immunity 2014 (40), 477-489).
Since RORγ plays an important role in the occurrence and development of various autoimmune diseases, the synthesis of a series of novel compounds to regulate the function of RORγ is of great importance. This can lay a foundation for the treatment of autoimmune diseases.